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Summary: Steroid hormone receptors are simultaneously active in many tissues and are capable of altering each other’s function. Estrogen receptor α (ER) and glucocorticoid receptor (GR) are expressed in the uterus, and their ligands have opposing effects on uterine growth. In endometrial tumors with high ER expression, we surprisingly found that expression of GR is associated with poor prognosis. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished in estrogen-induced endometrial hyperplasia. We observed low genomic-binding site overlap when ER and GR are induced with their respective ligands; however, upon simultaneous induction they co-occupy more sites. GR binding is altered significantly by estradiol with GR recruited to ER-bound loci that become more accessible upon estradiol induction. Gene expression responses to co-treatment were more similar to estradiol but with additional regulated genes. Our results suggest phenotypic and molecular interplay between ER and GR in endometrial cancer. : Estrogen receptor α (ER) and glucocorticoid receptor (GR) are expressed in the uterus and have differential effects on growth. Vahrenkamp et al. find that expression of both receptors is associated with poor outcome in endometrial cancer and that simultaneous induction of ER and GR leads to molecular interplay between the receptors. Keywords: estrogen receptor, glucocorticoid receptor, endometrial cancer

Cancer stem cells (CSCs) are a small subset of cancer cells responsible for maintenance and progression of several types of cancer. Isolation, propagation, and the differentiation of CSCs in the proper stem niches expose the intrinsic difficulties for further studies. Here we show that induced cancer like stem cells (iCLSCs) can be generated by in vitro oncogenic manipulation of mouse embryonic stem cells (mESCs) with well-defined oncogenic elements; SV40 LTg and HrasV12 by using a mouse stem virus long terminal repeat (MSCV-LTR)-based retroviral system. The reprogrammed mESCs using both oncogenes were characterized through their oncogenic gene expression, the enhancement of proliferation, and unhampered maintenance of stem properties in vitro and in vivo. In addition, these transformed cells resulted in the formation of malignant, immature ovarian teratomas in vivo. To successfully further expand these properties to other organs and species, more research needs to be done to fully understand the role of a tumor- favorable microenvironment. Our current study has provided a novel approach to generate induced cancer like stem cells through in vitro oncogenic reprogramming and successfully initiated organ-specific malignant tumor formation in an orthotopic small animal cancer model.

Checkpoint blockade immunotherapies harness the host's own immune system to fight cancer, but only work against tumors infiltrated by swarms of pre-existing T cells. Unfortunately, most cancers to date are immune-deserted. Here, we report a polymer-assisted combination of immunogenic chemotherapy and PD-L1 degradation for efficacious treatment in originally non-immunogenic cancer. "Priming" tumors with backbone-degradable polymer-epirubicin conjugates elicits immunogenic cell death and fosters tumor-specific CD8+ T cell response. Sequential treatment with a multivalent polymer-peptide antagonist to PD-L1 overcomes adaptive PD-L1 enrichment following chemotherapy, biases the recycling of PD-L1 to lysosome degradation via surface receptor crosslinking, and produces prolonged elimination of PD-L1 rather than the transient blocking afforded by standard anti-PD-L1 antibodies. Together, these findings established the polymer-facilitated tumor targeting of immunogenic drugs and surface crosslinking of PD-L1 as a potential new therapeutic strategy to propagate a long-term antitumor immunity, which might broaden the application of immunotherapy to immunosuppressive cancers., Competing Interests: Conflict of Interest J.K. and J.Y. are co-inventors of US Patent 9,289,510 related to KT-1; L.L., J.K., and J.Y. are co-inventors of a patent application related to combination chemo- and immunotherapy. The University of Utah licensed both to TheraTarget. Inc.

Purpose: Treating uterine fibroids with less invasive therapies such as magnetic resonance-guided focused ultrasound (MRgFUS) is an attractive alternative to surgery. Treatment planning can improve MRgFUS procedures and reduce treatment times, but the tissue properties that currently inform treatment planning tools are not adequate. This study aims to develop an ex vivo uterine fibroid model that can emulate the in vivo environment allowing for characterization of the uterus and fibroid MR, acoustic, and thermal tissue properties while maintaining viability for the necessary postsurgical histopathological assessments., Methods: Women undergoing a hysterectomy due to fibroid-related symptoms were invited to undergo a preoperative pelvic MRI and to permit postoperative testing of their uterine specimen. Patients that declined or could not be scheduled for a pre-operative MRI were still able to allow post-operative testing of their excised tissue. Following surgical removal of the uterus, nonmorcellated tissues were reperfused with a Krebs-Henseleit buffer solution. An MR-compatible perfusion system was designed to maintain tissue viability inside the MR suite during scanning. MR imaging protocols utilized preoperatively were repeated on whole sample, reperfused ex vivo uterus specimens. Thermal properties including thermal diffusivity and thermal conductivity of the uterus and fibroids were determined using an invasive needle sensor device in 50% of the specimens. Acoustic property measurements (density, speed of sound and attenuation) were obtained for approximately 20% of the tissue samples using both through-transmission and radiation force balance techniques. Differences between fibroid and uterus and in vivo and ex vivo measurements were evaluated with a two-tailed Student t test., Results: Fourteen patients participated in the study and measurements were obtained from 22 unique fibroids. Of the 16 fibroids available for preoperative MRI testing, 69% demonstrated classic hypo-intensity relative to the myometrium, with the remainder presenting with iso- (25%) or hyper-intensity (6%). While thermal diffusivity was not significantly different between fibroid and myometrium tissues (0.217 ± 0.047 and 0.204 ± 0.039 mm 2 /s, respectively), the acoustic attenuation in fibroid tissue was significantly higher than myometrium (0.092 ± 0.021 and 0.052 ± 0.023 Np/cm/MHz, respectively). When comparing in vivo with ex vivo MRI T1 and T2 measurements in fibroids and myometrium tissue, the only difference was found in the fibroid T2 property (P < 0.05). Finally, the developed perfusion protocol successfully maintained tissue viability in ex vivo tissues as evaluated through histological analysis., Conclusions: This study developed an MR-compatible extracorporeal perfusion technique that effectively maintains tissue viability, allowing for the direct measurement of patient-specific MR, thermal, and acoustic property values for both fibroid and myometrium tissues. These measured tissue property values will enable further development and validation of treatment planning models that can be utilized during MRgFUS uterine fibroid treatments., (© 2019 American Association of Physicists in Medicine.)